Throughout this application, various references ace referred to within parentheses. Disclosure of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
.alpha.-Adrenergic receptors (Lomasney, J. W. et al , Biochim. Biophy. Acta 1991, 1095, 127) are cell membrane proteins located in both the peripheral and central nervous systems. They belong to a diverse family of structurally related receptors which contain seven putative transmembrane helices and couple to intracellular guanine nucleotide binding proteins (G-proteins). These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many .alpha.-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (for nasal decongestion), medetomidine (for veterinary analgesia), UK-14,304 and apraclonidine (for glaucoma). .alpha.-Adrenergic drugs canr be divided into two disinct classes: agonists (like clonidine and naphazoline) which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagorists (like phenoxybenzamine and prazosin) which act to block the effects of norepinephrine. However, many of these drugs, though effective, also produce undesirable side effects. For example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects.
Prior to 1977, only one .alpha.-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two .alpha.-adrenergic receptors .alpha..sub.1 and .alpha..sub.2 existed. Since 1988, new techniques in molecular biology have led to the identification of at least six .alpha.-adrenergic receptors--a.sub.1a, .alpha..sub.1b, .alpha..sub.1c, .alpha..sub.2a, .alpha..sub.2b and .alpha..sub.2c (Bylund, D. B., FASEB J. 1992, 6, 832). In addition, current .alpha..sub.2 -adrenergic drugs are not selective for any particular .alpha..sub.2 -adrenergic receptor subtype. This lack of selectivity likely contributes to the untoward side effect of these drugs.
.alpha..sub.2 receptors are located both presynaptically at nerve terminals and postsynaptically as in vascular smooth muscles, platelets, pancreatic .beta.-cells, and fat cells. Activation of the presynaptic receptors inhibit the release of norepinephrine by a negative feedback mechanism. Blockade of these receptors would therefore increase the release of norepinephrine.
It is believed that .alpha..sub.2 receptors can modulate pain. Indeed, the effects of .alpha..sub.2 agonists on analgesia, anesthesia and sedation have been well documented (Pertovaara, P., Progress in Neurobiology, 1993, 40, 691). For example, systemic administration of clonidine has been shown to produce antinociception in various species including human patients in addition to its well known sedative effects. Intrathecal and epidural administration of clonidine has also proved effective in producing analgesia. Another agonist, medetomidine, which has better .alpha..sub.2 /.alpha..sub.1 selectivity and is more potent at .alpha..sub.2 receptors than clonidine, has been shown in humans to be effective for ischemic pain even though the doses were high enough to produce sedation and considerable decrease in blood pressure.
However, in anesthetic practice, the sedative effect of .alpha..sub.2 agonists is regarded as a good component of premedication.
Another beneficial effect of .alpha..sub.2 agonists is their ability to potentiate the anesthetic action and hence to reduce the anesthetic requirements of other agents during surgery (Ghingnone, M. et al., Anesthesiology 1986, 64, 36).
Other potential uses of .alpha..sub.2 agonists including lowering intraocular pressure, treating hypertension, alcohol and drug withdrawal, rheumatoid arthritis, ischemia migraine, cognitive deficiency, spasticity, diarrhea and nasal congestion (Cossement, E. et al., U.S. Pat. No. 4,923,865, 1990).
This invention is directed to imidazole and midazoline compounds which are selective agonists for human .alpha..sub.2 receptors. This invention is also related to the use of these compounds for treating disorders involving inhibition or lack of activation of .alpha..sub.2 adrenergic receptors such as hypertension, pain, glaucoma, alcohol and drug withdrawal, rheumatoid arthritis, ischemia, migraine, cognitive deficiency, spasticity, diarrhea and nasal congestion.